Aging is associated with an increased incidence of type 2 diabetes mellitus. On studying the characteristics of the age-related decline in insulin secretion that occurs with aging, it appears that the abnormality in insulin secretion from beta cells of the pancreas that occurs in diabetes is an exaggeration of normal aging processes, coupled with increasing demand for insulin release in the setting of insulin resistance. There is a decrease, with age, in insulin synthesis and storage of insulin, a decrease in the ability of the beta cells to replicate and the proteins which sense the prevailing levels of glucose are also decreased. We showed that these changes could be reversed with continuous administration of GLP-1 using an ALZET osmotic pump (1003D) implanted subcutaneously in the neck for 5 days in rodents. Insulin mRNA was increased 3-fold in the GLP-1 infused animals. Even the old rats which have a lower amount of mRNA (50% lower) for insulin than young rats had a 3-fold increase in insulin mRNA. The abnormality in insulin secretion with aging was also normalized by this treatment (J. Clin. Invest. 99:2883-2889, 1999). Of great interest is the fact that there was an increase in beta cell mass after chronic treatment with GLP-1, a naturally occuring peptide produced and released from the gut in response to food. GLP-1 also causes stem cells to proliferate which then differentiate into islet-like cells. This occured in cells of both the acinar and ductal tissue. This phenomenon has not been shown with any previous treatment. It will require further study to determine the mechanism by which GLP-1 activates islet specific genes and it has implications for treating pancreatitis and type 1 diabetes, also. One specific gene which GLP-1 largely influences is IPF-1 (Islet-pancreatic factor). It is necessary for pancreatic development and in adult beta- cells, it regulates the insulin, glucose transporter 2 and glucokinase genes. We recently reported the GLP-1 plays a major role in regulating levels and translocation to the nucleus of IPF-1 (Endocrinology 140:4904-4907, 1999). Using an acninar cell line, AR42J cells, we have shown that the cells can become insulin-producing when treated with GLP-1, and they become responsive to glucose (Diabetes 48, 1999). We have investigated the intracellular signals involved in the GLP-1- induced differentiation of AR42J cells and found that it is dependent on the continuous activation of the MAP kinase pathway. We also completed studies in duct cells lines to see if the same pathways are involved (submitted to Endocrinology) as well as completed in vivo studies in rodents (submitted to Diabetes). We are continuing our studies on the mechanisms whereby GLP-1 actually regulates IPF-1 and if it regulates other transcription factors. A major thrust of our research is to isolate the epithelial stem cells of the pancreas (which have the capacity to become islets cells, duct cells and acinar cells) and study the factors involved. - Aging, Beta cells, Insulin, GLP-1, MAP kinase, Transcription factors